Gardier A M, Malagié I, Trillat A C, Jacquot C, Artigas F
Faculté de Pharmacie, Université Paris-Sud, Chatenay-Malabry, France.
Fundam Clin Pharmacol. 1996;10(1):16-27. doi: 10.1111/j.1472-8206.1996.tb00145.x.
Although a new generation of selective serotonin reuptake inhibitors (SSRIs) has been introduced in therapeutics as antidepressant drugs, a two to four week lag period still occurs between starting treatment with SSRIs and the onset of therapeutic effects in man. In vivo cerebral microdialysis can be used to measure extracellular concentrations of serotonin (5-hydroxytryptamine, 5-HT), which reflect intrasynaptic events. With the coupling of this new experimental method to very sensitive analytical assays such as liquid chromatography with electrochemical detection, it has recently been possible to obtain two major arguments supporting the hypothesis that somatodendritic 5-HT1A autoreceptors situated in the raphe nuclei play an important role in the mechanism of action of SSRIs. First, in the rat, single administration of SSRIs at low doses comparable to those used therapeutically increases extracellular 5-HT concentrations in the vicinity of the cell body and the dendrites of serotoninergic neurones of the raphe nuclei. This effect is more marked than that observed in regions rich in nerve endings (frontal cortex). The magnitude of the activation of the serotoninergic neurotransmission depends on the brain area studied and the dose of the SSRIs administered to rats. This could be explained by simultaneous activation of somatodendritic 5-HT1A autoreceptors by endogenous 5-HT in the raphe nuclei, thereby limiting the corticofrontal effects of the antidepressant. Second, SSRIs cause a larger increase in extracellular 5-HT concentrations in the nerve endings when administered chronically: 5-HT autoreceptors may have gradually desensitized during the 2-4 weeks of treatment with SSRIs. Preliminary studies of patients with depression appear to confirm these experimental results, as co-administration of a 5-HT1A autoreceptor antagonist and a SSRI accelerated the onset of the antidepressant effect (< 1 week).
尽管新一代选择性5-羟色胺再摄取抑制剂（SSRI）已作为抗抑郁药应用于治疗，但从开始使用SSRI治疗到其在人体产生治疗效果之间仍存在2至4周的延迟期。体内脑微透析可用于测量血清素（5-羟色胺，5-HT）的细胞外浓度，该浓度反映突触内事件。随着这种新实验方法与非常灵敏的分析检测方法（如电化学检测液相色谱法）相结合，最近有可能获得两个主要论据，支持位于中缝核的树突体5-HT1A自身受体在SSRI作用机制中起重要作用这一假说。首先，在大鼠中，以与治疗剂量相当的低剂量单次给予SSRI，可增加中缝核5-羟色胺能神经元细胞体和树突附近的细胞外5-HT浓度。这种效应比在富含神经末梢的区域（额叶皮质）观察到的效应更明显。5-羟色胺能神经传递的激活程度取决于所研究的脑区以及给予大鼠的SSRI剂量。这可以通过中缝核内内源性5-HT同时激活树突体5-HT1A自身受体来解释，从而限制了抗抑郁药的皮质额叶效应。其次，长期给予SSRI时，其在神经末梢引起的细胞外5-HT浓度升高幅度更大：在使用SSRI治疗的2至4周内，5-HT自身受体可能已逐渐脱敏。对抑郁症患者的初步研究似乎证实了这些实验结果，因为联合给予5-HT1A自身受体拮抗剂和SSRI可加速抗抑郁作用的起效（<1周）。
